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  • Desformylflustrabromine hydrochloride br Results and discuss

    2021-10-13


    Results and discussion
    Conclusion In the continued SAR study of our previous heterocycle scaffolds represented by Desformylflustrabromine hydrochloride 2, we focused especially on improving their drug-like physicochemical properties directed by lipophilicity, LE and LLE. After explored several heterocyclic scaffolds, the potent FFA1 agonists bearing 3, 5-dimethylisoxazole scaffold was identified. Further structure-based optimization and chiral resolution, leading to the discovery of (S)-enantiomer 11, the most potent agonist (EC50 = 7.9 nM) in this series with improved lipophilicity (LogD7.4: 1.93), LE and LLE values (0.32 and 6.2, respectively). PK evaluation in rats indicated excellent PK profiles and >1.8-fold higher plasma exposure of 11 compared to TAK-875, the most promising candidate in this field. Interestingly, the in vitro activity and PK properties of compound 11 were better than TAK-875, but the anti-diabetic effect of compound 11 was inferior to that of TAK-875. Further studies on the identification of in vitro/in vivo correlation are currently in progress and will be presented in due course.
    Experimental section
    Acknowledgement This study was supported by grants from the National Natural Science Foundation of China (Grants 81673299 and 81273376).
    Introduction As the life expectancy continue to rise in the world especially in the developed countries, the proper care for aged skin has become a medical concern for the growing elderly population. Skin, a truly sophisticated and dynamic organ, is the largest organ of human body and the primary organ in the integumentary system (Iqbal, Ali, & Baboota, 2018). Skin plays vital roles on defense against foreign organisms, homeostatic regulation, prevention of percutaneous loss of fluid, electrolytes, and proteins, waste removal, production of vitamin D, temperature maintenance, sensory perception and immune surveillance (Sorg, Tilkorn, Hager, Hauser, & Mirastschijski, 2017). Over the years, metabolic processes and harmful environmental factors cause skin aging, which is inevitable but manageable. Clinical manifestations of aged skin may include deep wrinkles, reduced elasticity, xerosis, uneven pigmentation, and benign neoplasms such as cherry angiomas (Dyer & Miller, 2018). The issue of skin aging is expected to become more serious based on the fact of prolonged life expectancy (Passeron & Picardo, 2017). One of the key physiological changes during skin aging is the decline in lipid content. Epidermal fat synthesis particularly cholesterol synthesis and the secretion of fat by sebaceous glands and keratinocytes are impaired over age (Ghadially et al., 1996, Pappas, 2009, Pappas et al., 2013). In terms of fatty acids, palmitoleic acid (C16:1, n-7), oleic acid (C18:1, n-9), and eicosatrienoic acid (ETA, C20:3, n-3) were reported to be the main fatty acids altered in aged skin (Kim et al., 2010). There are emerging evidence in PubMed showing that the enrichment of certain fatty acids and sterols can differentially influence the integrity of skin (Kiezel-Tsugunova et al., 2018, Souyoul et al., 2018). In this review, we will first briefly introduce skin aging and the role of lipids in skin function. Then, the recent findings on the modulating role of fatty acids and sterols in skin aging and potential mechanisms will be summarized.
    Overview of skin structure and cause of skin aging The human skin can be divided in to three layers: epidermis, dermis, and hypodermis. Epidermis is the outer non-vascularized layer, which is colonized by keratinocytes, melanocytes, Langerhans cells, and T cells. The dermis is the middle thick layer of skin, which is rich in extracellular matrix and consists of large amount of collagen, elastin, proteoglycans, and fibronectin. The dermis contains hair follicles, sweat glands, sebaceous glands, apocrine glands, Desformylflustrabromine hydrochloride lymphatic vessels, blood vessels, and nerves. A variety of cells can be found in dermis including fibroblasts, mast cells, neutrophils, macrophages, eosinophils, T cells, B cells, and dendritic cells. These cell populations are highly dynamic and cell trafficking constantly occurs when encountering stimuli. The hypodermis is composed of adipocytes, fibroblasts, macrophages, nerves, and blood vessels (Pasparakis, Haase, & Nestle, 2014).